This application was filed under 35 USC xc2xa7371, of PCT Application No. PCT/JP99/04934, having an International Filing Date of Sep. 10, 1999, claiming benefit of Japanese application no. 10-279347, filed on Sep. 14, 1998.
The present invention relates to xcfx89-substituted phenyl-prostaglandin E derivatives. More particularly, the present invention relates to
(1) xcfx89-substituted phenyl-prostaglandin E derivatives of formula (I) 
xe2x80x83(wherein all symbols have the same meaning as described hereafter.),
(2) a process for the preparation thereof and
(3) a medicament comprising them as active ingredient.
Prostaglandin E2 (abbreviated as PGE2 hereafter.) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE2 has cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity, etc.
In the recent studies, it was found that PGE2 receptor was divided into some subtypes which possess different physiological roles from each other. At present, four main receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 (Negishi M. et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
The present inventors investigated to find new compounds which bind on each receptor specifically, so that we found that the compounds of the present invention could bind selectively on EP4 subtype receptor and achieved the present invention.
The compounds of the present invention of formula (I) bind strongly on subtype EP4 and therefore are useful for the prophylaxis and/or treatment of immune diseases (autoimmune diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren""s syndrome, arthritis, rheumatoid arthritis, systemic lupus erythematosus, etc.), post-transplantation graft rejection, etc.), asthma, abnormal bone formation, neurocyte death, pulmopathy, hepatopathy, acute hepatitis, nephritis, renal insuffiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, pain induced by ambustion, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, Still""s diseases, Kawasaki diseases, burn, systemic granuloma, ulcerative colititis, Crohn""s diseases, hypercytokinemia at dialysis, multiple organ failure, shock, etc. They are also related with sleeping disorders and platelet coagulations, and therefore they are thought to be applicable to these diseases.
The compounds of the present invention of formula (I) bind weakly on other PG receptors including other subtypes and do not express other effects, and therefore it is probable that those compounds will be medical agents having less side-effects.
On the other hand, a lot of PG compounds wherein phenyl group is introduced in the xcfx89-chain are known, e.g. the following patent applications. The comments in the parenthesis show the use of the compounds.
9-oxo type: JP kokai sho 49-92053 (i.e. U.S. Pat. No. 4,036,832) (hypotensive effect etc.),
9-chloro substituted type: JP kokai sho 56-92860 (i.e. U.S. Pat. No. 4,444,788) (luteal recessive effect etc.),
9-fluoro substituted type: JP kokai sho 58-8059 (i.e. U.S. Pat. No. 4,454,339) (luteal recessive effect etc.),
11-deoxy type: JP kokai sho 53-135956 (i.e. U.S. Pat. No. 3,932,389) (intermediates for prostaglandin having hypotensive effect etc.).
JP Kokai Sho 49-92053 (i.e U.S. Pat. No. 4,036,832) discloses that the following compounds have a hypotensive effect, stimulating effect against smooth muscle, peptic ulcers, bronchodilator effect and therefore they are useful.
A compound of formula (A) 
(wherein Ar is xcex1- or xcex2-furyl, xcex1- or xcex2-thienyl, xcex1- or xcex2-naphthyl, phenyl,
3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl or phenyl monosubstituted by halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy,
nA is 0 or an integer of 1xcx9c5, with the proviso that when Ar is phenyl, substituted
phenyl or naphthyl, then nA is 0 or 1,
R is hydrogen atom or lower alkyl,
W is a bond or a cis double bond,
Z is a bond or a trans double bond,
M is keto, 
N and L are taken together to form a bond or when L is hydrogen, N is selected so as to complete A, E or F prostaglandin structure), or lower alkanoyl, formyl or benzoyl ester of free hydroxy group in C9, C11 or C15 position and a pharmaceutically acceptable salt thereof.
The specification provides specific PGE2 compounds in which phenyl substituted by alkyl or alkoxy is introduced in the xcfx89-chain; i.e. the compounds of examples 55 and 72 of the following formula.
Example 55: 
Example 72: 
The present invention consists in, as described hereafter, the fact that the present inventors have found that PGE compounds in which the xcfx89-chain includes phenyl group substituted by particular substituents bind strongly on EP4 and bind weakly on the other PG receptors including other subtypes than EP4. In other words, the present inventors have found that adoption of particular groups maintained EP4 activity and the selectivity for EP4 over other receptors is improved, to complete the invention.
The present invention relates to
(1) an xcfx89-substituted phenyl prostaglandin E derivative of formula (I) 
xe2x80x83(wherein A is C2xcx9c8 alkylene, C2xcx9c8 alkenylene, C1xcx9c4 alkylene-phenylene, or
C2xcx9c4 alkenylene-phenylene,
R1 is hydroxy, C1xcx9c6 alkyloxy, C1xcx9c6 alkyloxy-C1xcx9c6 alkyloxy, HOxe2x80x94C1xcx9c6 alkyloxy or a formula of NR6R7 (wherein R6 and R7 are each independently hydrogen atom or C1xcx9c4 alkyl),
R2 is oxo, halogen or a group of formula R8xe2x80x94COO-(wherein R8 is hydrogen, C1xcx9c4 alkyl, phenyl or phenyl(C1xcx9c4 alkyl), C1xcx9c4 alkyloxy, HOOCxe2x80x94C1xcx9c4 alkyl, C1xcx9c4 alkyloxy-carbonyl-C1xcx9c4 alkyl, HOOCxe2x80x94C2xcx9c4 alkenyl or C1xcx9c4 alkyloxy-carbonyl-C2xcx9c4 alkenyl),
R3 is hydrogen atom or hydroxy,
R4 is C1xcx9c4 alkylene,
R5 is phenyl substituted by the following groups:
i) 1xcx9c3 groups selected from
C1xcx9c4 alkyloxy-C1xcx9c4 alkyl,
C2xcx9c4 alkenyloxy-C1xcx9c4 alkyl,
C2xcx9c4 alkynyloxy-C1xcx9c4 alkyl,
C3xcx9c7 cycloalkyloxy-C1xcx9c4 alkyl,
C3xcx9c7 cycloalkyl(C1xcx9c4 alkyloxy)-C1xcx9c4 alkyl,
phenyloxy-C1xcx9c4 alkyl,
phenyl-C1xcx9c4 alkyloxy-C1xcx9c4 alkyl,
C1xcx9c4 alkylthio-C1xcx9c4 alkyl,
C2xcx9c4 alkenylthio-C1xcx9c4 alkyl,
C2xcx9c4 alkynylthio-C1xcx9c4 alkyl,
C3xcx9c7 cycloalkylthio-C1xcx9c4 alkyl,
C3xcx9c7 cycloalkyl(C1xcx9c4 alkylthio)-C1xcx9c4 alkyl,
phenylthio-C1xcx9c4 alkyl and
phenyl-C1xcx9c4 alkylthio-C1xcx9c4 alkyl,
ii) C1xcx9c4 alkyloxy-C1xcx9c4 alkyl and C1xcx9c4 alkyl,
C1xcx9c4 alkyloxy-C1xcx9c4 alkyl and C1xcx9c4 alkyloxy,
C1xcx9c4 alkyloxy-C1xcx9c4 alkyl and hydroxyl,
C1xcx9c4 alkyloxy-C1xcx9c4 alkyl and halogen,
C1xcx9c4 alkylthio-C1xcx9c4 alkyl and C1xcx9c4 alkyl,
C1xcx9c4 alkylthio-C1xcx9c4 alkyl and C1xcx9c4 alkyloxy,
C1xcx9c4 alkylthio-C1xcx9c4 alkyl and hydroxy or
C1xcx9c4 alkylthio-C1xcx9c4 alkyl and halogen,
iii) halo-C1xcx9c4 alkyl or hydroxy-C1xcx9c4 alkyl, or
iv) C1xcx9c4 alkyl and hydroxy; and is a bond or a double bond, and when R2 is a group of formula R8xe2x80x94COOxe2x80x94, R1 is C1xcx9c6 alkoxy, C1xcx9c6 alkyloxy-C1xcx9c6 alkyloxy or HOxe2x80x94C1xcx9c6 alkyloxy and 8-9 position is a double bond), a non-toxic salt thereof or a cyclodextrin clathrate thereof,
(2) a process for the preparation thereof and
(3) a medicament comprising it as active ingredient.
In the formula (I), C1xcx9c4 alkyl in R5, R6, R7 and R9 is methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), C1xcx9c6 alkyl in R1 is methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
In the formula (I), C1xcx9c4 alkylene in R4 and A is methylene, ethylene, trimethylene, tetramethylene and isomers thereof.
In the formula (I), C2xcx9c8 alkylene represented by A is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof.
In the formula (I), C2xcx9c8 alkenylene represented by A includes one or two double bond(s) in itself, for example, vinylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, pentadienylene, hexadienylene, heptadienylene, octadienylene and isomers thereof.
In the formula (I), C2xcx9c4 alkenylene in A is vinylene, propenylene, butenylene and isomers thereof.
In the formula (I), C2xcx9c4 alkenyl in R5 and R8 is vinyl, propenyl, butenyl and isomers thereof.
In the formula (I), C2xcx9c4 alkynyl in R5 is ethynyl, propynyl, butynyl and isomers thereof.
In the formula (I), C3xcx9c7 cycloalkyl in R8 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the formula (I), halogen in R2 and R8 is fluorine, chlorine, bromine and iodine.
In the present invention, as may be easily understood by those skilled in the art, 
indicates a single bond or a double bond, unless otherwise specified, the symbol: 
indicates that the substituent attached thereto is in front of the sheet (xcex2-position), 
indicates that the substituent attached thereto is behind the sheet (xcex1-position), 
indicates that the substituent attached thereto is in xcex2-position or xcex1-position or a mixture thereof.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl and alkylene include straight-chain and branched-chain ones. Isomers in the double bonds, rings, fused rings (e.g. E, Z, cis, trans isomers), isomers generated by the existence of asymmetric carbon atom(s) (e.g. R, S isomers, xcex1, xcex2 isomers, enantiomers, diastereomers), optically active isomers having optically rotatory power (D, L, d, I isomers), polar isomers separated by chromatography (more polar, less polar isomers), equilibrium compounds, arbitrary ratios of these compounds, racemic mixtures are all included in the present invention.
In the formula (I), the group of formula 
is preferably, 
In the formula (I), hydroxy in the 15-position is preferably attached as the xcex1-configuration.
In the formula (I), in the alkylene of R4, methylene is most preferable.
In the formula (I), the position of the substituent of phenyl in R5 is preferably the 3-position, the combination of 3- and 4-position and the combination of 3- and 5-position.
In the compounds of the present invention of formula (I), the compounds described in the examples, the following compounds and corresponding esters, amides and 8-acylated compounds thereof are preferable.
The compounds of the present invention of formula (I) may be converted into the corresponding salts by conventional methods. Non-toxic and water-soluble salts are preferable. Appropriate salts are described hereafter; salts of alkali metals (e.g. potassium, sodium), salts of alkaline-earth metals (e.g. calcium, magnesium), ammonium salts, salts of pharmaceutically acceptable organic amines (e.g. tetramethyl ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine).
xcfx89-Substituted phenyl-prostaglandin E derivatives of formula (I) may be converted into cyclodextrin clathrates using xcex1-, xcex2- or xcex3-cyclodextrin or a mixture thereof, by the methods described in the specification of Japanese Kokoku No. 50-3362, ibid. 52-31404 (i.e. GB Patent Nos. 1351238, 1419221) or Japanese Kokoku No. 61-52146. Converting them into cyclodextrin clathrates serves to increase the stability and solubility in water, and therefore it is convenient for pharmaceutical use.
Processes for the preparation of the compounds of the present invention
(a) Among the compounds of formula (I), a compound wherein R1 is C1xcx9c6 alkyloxy, C1xcx9c6 yloxy-C1xcx9c6 alkyloxy or HOxe2x80x94C1xcx9c6 alkyloxy, i.e. a compound of formula (Ia) 
xe2x80x83(wherein R11 is C1xcx9c6 alkyloxy, C1xcx9c6 alkyloxy-C1xcx9c6 alkyloxy or HOxe2x80x94C1xcx9c6 alkyloxy and the other symbols have the same meanings as described hereinbefore) may be prepared by subjecting to a deprotection reaction under acidic conditions a compound of formula (II) 
xe2x80x83(wherein R12 is C1xcx9c6 alkyloxy, C1xcx9c6 alkyloxy-C1xcx9c6 alkyloxy or (a protective group for hydroxy removable under acidic conditions)-Oxe2x80x94C1xcx9c6 alkyloxy, R31 is hydrogen or a protected form of hydroxy in which the protective group is removable under acidic conditions, R10 is a protective group for hydroxy removable under acidic conditions, R51 has the same meaning as R5, but hydroxy in the group of R51 is protected by a protective group removable under acidic conditions and the other symbols have the same meanings as described hereinbefore).
Protective groups for hydroxy removable under acidic conditions include, for example, t-butyldimethylsilyl, triphenylmethyl, tetrahydropyran-2-yl, etc.
Hydrolysis under acidic conditions is known, for example, it is carried out in a water-miscible organic solvent (e.g. tetrahydrofuran, methanol, ethanol, dimethoxyethane, acetonitrile or a mixture thereof, etc.), using inorganic acid (e.g. hydrochloric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid-pyridine, etc.) or an organic acid (e.g. acetic acid, tosyl acid, trichloroacetic acid, etc.) at a temperature of 0xcx9c50xc2x0 C.
(b) Among the compounds of formula (I), a compound wherein R1 is hydroxy, i.e. a compound of formula (Ib) 
xe2x80x83(wherein all symbols have the same meaning as described hereinbefore) may be prepared by subjecting to hydrolysis reaction using an enzyme or a hydrolysis reaction under alkaline conditions a compound of formula (Ia) 
xe2x80x83(wherein all symbols have the same meaning as described hereinbefore). Hydrolysis using an enzyme is known, for example, it may be carried out in a mixture of water-miscible organic solvent (e.g. ethanol, dimethylsulfoxide, etc.) and water, in the presence or absence of a buffer, using hydrolase (esterase, lipase etc.) at a temperature of 0xcx9c50xc2x0 C.
Hydrolysis under alkaline conditions is known, for example, it may be carried out in a mixture of a water-miscible organic solvent (e.g. ethanol, tetrahydrofuran (THF), dioxane, etc.) using an aqueous solution of an alkali (sodium hydroxide, potassium hydroxide, potassium carbonate, etc.) at a temperature of xe2x88x9210xcx9c90xc2x0 C.
(c) Among the compounds of formula (I), a compound wherein R1 is NR6R7, i.e. a compound of formula (Ic) 
xe2x80x83(wherein all symbols have the same meaning as described hereinbefore) may be prepared by subjecting to an amidation reaction a compound of formula (Ib) 
xe2x80x83(wherein all symbols have the same meaning as described hereinbefore) and a compound of formula (III)
xe2x80x83HNR6R7xe2x80x83xe2x80x83(III)
xe2x80x83(wherein ail symbols have the same meaning as described hereinbefore).
Amidation reaction is known, for example, it is carried out in an inert organic solvent (e.g. THF, methylene chloride, benzene, acetone, acetonitrile or a mixture thereof, etc.) in the presence or absence of a tertiary amine (dimethylaminopyridine, pyridine, triethylamine, etc.), using a condensing reagent (1,3-dichlorohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), etc.) at a temperature of 0xcx9c50xc2x0 C.
The compound of formula (III) is a known compound or may be prepared by known methods easily.
The compound of formula (II) may be prepared according to the following schemes 1, 2, 3 or 6.
Moreover, the compounds of formula (Ia), (Ia-1) and (Ib) may be synthesized by the schemes 4 or 5.
The symbols described in the schemes have the following meaning or the same meaning as described hereinbefore:
t-Bu: t-butyl,
Ms: methanesulfonyl,
n-Bu: normal butyl,
Ts: p-toluenesulfonyl,
X: halogen atom,
R21: halogen atom,
R22: acyl,
A1: C1xcx9c7 alkylene, C2xcx9c7 alkenylene,
C1xcx9c3 alkylene-phenylene or C2xcx9c3 alkenylene-phenylene,
A2: C2xcx9c8 alkylene or C1xcx9c4 alkylene-phenylene.
In each scheme, the process for the preparation of 15xcex1 isomer is illustrated, but 15xcex2 isomer and a mixture of 15xcex1 and 15xcex2 isomers may be also synthesized depending on the choice of reduction method, with or without separation, depending on the choice of starting materials 
Each reaction in the above reaction schemes is carried out by known methods. In the above reaction schemes, the compounds of formulae (IV), (V), (XIX), (XIX), X(X), (XXXII) and (XXXVII) are known per se or may be prepared by known methods easily. For example, among the compounds of formula (IV), a compound wherein R31 is tetramethylsilyloxy, A is hexenylene and R12 is ethoxy is described in JP kokai sho 58-39660 (i.e. U.S. Pat. No. 4,363,817); among the compounds of formula (XIX), a compound wherein R12 is methoxy, R22 is acetyl, R31 is 2-tetrahydropyranyloxy and A is hexenylene is described in JP kokai sho 52-27753 (i.e. U.S. Pat. No. 4,180,675). The other starting materials and reagents in the present invention are known per se or may be prepared by known methods.
In each reaction of the present specification, reaction products may be purified by conventional techniques. For example, purification may be carried out by distillation under atmospheric or reduced pressure, by high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, by washing or by recrystallization, etc. Purification may be carried out after each reaction, or after a series of reactions.
The compounds of the present invention of formula (I) bind strongly and act on EP4 receptor which is PGE2 receptor subtype.
For example, in the laboratory the effects of the compounds of the present invention were confirmed by binding assay using expression cell of prostanoids receptor subtype.
(i) Binding assay using Expression cell of prostanoids receptor subtype
The preparation of membrane fraction was carried out according to the method of Sugimoto et al. [J. Biol. Chem., 267, 6463-6466 (1992)], using expression CHO cell of the prostanoids receptor subtype (mouse EP1, EP2, EP3xcex1, EP4 and human IP).
The standard assay mixture containing membrane fraction (0.5 mg/ml) and [3H]-PGE2 in a final volume of 200 xcexcl was incubated for 1 hour at room temperature. The reaction was terminated by addition of ice-cooled buffer (3 ml). The mixture was filtered through a GF/B glass filter under reduced pressure. The radioactivity associated with the filter was measured by liquid scintillation counting.
Kd and Bmax values were determined from Scatchard plots [Ann. N. Y. Acad. Sci., 51, 660 (1949)]. Non-specific binding was calculated as the binding in the presence of an excess (2.5 xcexcM) of unlabeled PGE2. In the measurement of 3H-PGE2 binding inhibitory activity, [3H]-PGE2 (2.5 nM) and various concentrations of the compounds of the present invention were added. The following buffer was used in all reactions.
Buffer ; 10 mM potassium phosphate (pH 6.0), 1 mM EDTA, 10 mM MgCl2, 0.1 M NaCl.
The dissociation constant Ki (xcexcM) of each compound was calculated by the following equation.
Ki=IC50/(1+([C]/Kd));
The results are shown in the Tables 19 and 20.
As shown above, it is clear that the compounds of the present invention bind strongly on subtype EP4 and weakly on the other PGE2 receptors (e.g. EP3).
The toxicity of the compounds of the present invention is very low and therefore, it is confirmed that these compounds are safe for pharmaceutical use.
The compounds of the present invention of formula (I) bind selectively and act on PGE2 receptor, especially on EP4 subtype receptor and therefore are useful for the prophylaxis and/or treatment of immune diseases (autoimmune diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren""s syndrome, arthritis, rheumatoid arthritis, systemic lupus erythematosus, etc.), post-transplantation graft rejection, etc.), asthma, abnormal bone formation, neurocyte death, pulmopathy, hepatopathy, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, pain induced by ambustion, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, Still""s diseases, Kawasaki diseases, burn, systemic granuloma, ulcerative colititis, Crohn""s diseases, hypercytokinemia at dialysis, multiple organ failure, shock, etc. They are also connected with sleeping disorders and platelet coagulations, and therefore they are thought to be useful for these diseases.
Among the compounds of the present invention of formula (I), the compounds which bind on other subtypes than EP4 weakly do not express other effect, and therefore it is probable that they will be those agents having less adverse effects.
For the purpose described hereinbefore, the compounds of the present invention of formula (I), non-toxic salts thereof and CD clathrates thereof may normally be administered systemically or topically, by oral or parenteral administration.
The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally from 1 xcexcg to 100 mg, by oral administration, from once up to several times per day, and from 0.1 xcexcg to 10 mg, by parenteral administration (preferably intravenously) from once up to several times per day, or by continuous administration for from 1 hour to 24 hours per day into vein.
As mentioned hereinbefore, the doses to be administered depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified hereinbefore may be used.
The compounds of the present invention may be administered in the form, for example, of solid compositions, liquid compositions or other compositions for oral administration, or injections, liniments or suppositories etc. for parenteral administration.
Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules etc.
Capsules include hard capsules and soft capsules.
In these solid compositions, one or more of the active compound(s) are admixed with at least one inert diluent, e.g. lactose, mannitol, mannit, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium metasilicate aluminate. The composition may comprise, according to the conventional manner, additives other than inert diluents, e.g. lubricating agents such as magnesium stearate, disintegrating agents such as cellulose calcium glycolate, agents to assist dissolution such as glutamic acid, aspartic acid. The tablets or pills may, if desired, be coated with film of gastric or enteric material such as sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl cellulose phthalate etc. or be coated with more than one film. Coating may include containment within capsules of absorbable materials such as gelatin.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) may be contained in inert diluent(s) commonly used in the art (e.g. purified water, ethanol). Besides inert diluents, such compositions may also comprise assisting agents (e.g. wetting agents, suspending agents), sweetening agents, flavoring agents, perfuming agents and preserving agents.
Other compositions for oral administration include spray compositions which comprise one or more of the active compound(s), prepared by methods known per se. Spray compositions may comprise stabilizing agents such as sodium sulfite hydride, isotonic buffers such as sodium chloride, sodium citrate or citric acid. For the preparation of such spray compositions, for example, the method described in the U.S. Pat. No. 2,868,691 or U.S. Pat. No. 3,095,355 may be used.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological salt solution. Non-aqueous solution and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol, POLYSORBATE80 (registered trademark) etc. These compositions may comprise assisting agents such as preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, agents assisting dissolution (e.g. glutamic acid, aspartic acid etc.). They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions which may be dissolved in sterile water or some other sterile solvent(s) for injection before use.
Other compositions for parenteral administration include liquids for external use, and ointment, endermic liniments, suppositories for rectal administration and pessaries for vaginal administration etc. which comprise one or more of active compound(s) and may be prepared by conventional methods.
The following reference examples and examples are intended to illustrate, but do not limit, the present invention. The solvents in parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations. The solvents in the parenthesis of NMR show the solvents used for measurement.